Compounds of the adrenal cortical hormone series and process of making same



Patented May 4;, 1948 COMPOUNDS OF THE ADRENAL OORTICAL HORMONE SERIESAND PROCESS OF MAK- ING SAME Tadeus Reichstein, Basel, Switzerland NDrawing. Application July 27, 1943, Serial No.

496,350. InSwitzerland October 7, 1942 1 17 Claims.

It is known that one or two acetoxy groups can be introduced in thea-position to a keto group by the action of lead tetra-acetate in asolution of glacial acetic acid (Dimroth and Schweitzer, Berichte derDeutschen Chemischen Gesellschaft, vol. 56, page 1375 [1925]). In thisWay it has been possible, for example, to convert acetone intoacetoxy-acetone and symmetrical diacetoxyacetone.

Thefirst application of this method to ketones of thecyclopentano-polyhydrophenanthrene se-' rise is described in U. S.Patents No. 2,230,772 and No. 2,230,773. In British Patent No. 524,006lead tetra-acylates with the exclusion of lead tetraacetate are used. Inthe said patents, progesterone is said to give a good yield of21-acyloxyprogesterones (desoxycorticosterone-acy1ates) by the describedreaction, a fact which has been disputed, however, by Reichstein andMontigel (Helvetica Chimica Acta, vol. 22, page 1212 [1939]). Theunfavourable course of the reaction was subsequently admitted by theinventors Erhardt, Ruschig and Aumiiller (Berichte der DeutschenChemischen Gesellschaft, vol. 72, page 2035 [1939]).

On applying the lead tetra-acylate method to A-pregnene-Z0-one-3-ol-acylate, ketol-acylates, namely A 3,21diacyloxy-pregnene-20-ones, are obtained in good yields. The latter are,however, biologically inactive and cannot be easily converted into thecorresponding active 3-keto compounds, the desoxycorticosteroneacylates.

It has now been found that compounds of the adrenal cortical hormoneseries can be obtained by treating compounds of thecyclopentanopolyhydrophenanthrene series which contain at least in the3-position a free nuclear hydroxyl group, in the 17-position an acylgroup with at' least one hydrogen atom in a-position to the keto group,and at the carbon atom 11 an oxo or a hydroxy group, a group convertibleinto a hydroxyl group by hydrolysis or a nuclear double bond (beingtherefore in 11,12- or 9,11-position), with lead tetra-acylates oraryl-iodoso-acylates, converting the nuclear hydroxyl group in the 3-position in a known manner into a keto group (if necessary aftertemporary protection of carbon double bonds which may be present),introducing, if desired, a double bond into the a-position to this ketogroup and finally treating with hydrolizing and/or esterifying agents.

The parent compounds for the present process may be saturated, orunsaturated at one or more places, and of any steric configuration. Theymay contain, in addition to the above mentioned substituents, freeesterified or etherized hydroxyl groups and keto groups, for example inthe 6,7 and/or 12, and also in the 17-position. Of the compoundsunsaturated in ring C, those with a double bond in the 11,12-position,particularly, and also in the 9,11 position can be used. The acyl, e. g.acetyl or propionyl, group at the 17 carbon atom may have in addition tothe necessary hydrogen atom at the u-position to the keto group, forexample, substituents such as acyl, or free or esterfied carboxylradicals. Such starting compounds can be prepared, for example, bymalonic-ester synthesis.

According to the present process the parent material is first treatedwith lead tetra-acylates such as lead tetra-acetate, tetra-propionate,tetra-butyrate, tetra-palmitate or tetra-benzoate. This reaction is bestcarried out in solvents or diluents, preferably in the carboxylic acidwhich corresponds to the acid radical of the lead tetraacylate used,namely in acetic, propionic, butyric or palmitic acid, etc., ifnecessary after the addition of inert solvents such as benzene.Surprisingly, it has been found that particularly good yields areobtained if the acetic acid used is mixed with some percents of waterand if the reaction is carried out at a temperature of about C. Insteadof lead tetra-acylates, aryl-iodoso-acylates, e. g.phenyl-iodoso-acetate can be used.

Free nuclear hydroxyl groups contained in the parent compounds,particularly that in the 3- position take, surprisingly enough,practically no part in the reaction and the presence of double bonds inunsaturated compounds does not lead to complications. In contrast to theprocess starting from compounds with a A -3-keto group,.

the first stage of the present process gives a very good yield. Theadvantage over the process which starts from 3-acylates consists of thefact that the ketol-esters obtained by the new process can easily beconverted into the corresponding highly active 3-ketones. The productsare in addition substituted in the ll-position or possess a double bondstarting from the ll-carbon atom and are therefore, as is known,particularly active in certain test methods.

. On working up further, the free 3-hydroxy1 group is converted into aketo group by the action of the usual oxidizing or dehydrogenatingagents, e. g. chromic acid in glacial acetic acid or permanganate, byheating with metals or metal oxides or by means of metal alcoholates ofpheno lates in the presence of carbonyl. compounds (acetone,cyclohexanoneetc.) or by decomposition by heat or triarylmethyl ethers..Carbon double bonds present may. betemporarily pro.- tected, ifnecessary, by addition and subsequent tity of oxidizing agent to reactor, in particular,

by using metal alcoholates or phenolates in the presence of carbonylcompounds. If no double bond is present in the lit-position to the3-lgeto,

group, it can be introduced in a known way e. g. by halogenisation andsubsequent elimination of hydrohalide.

On the products obtained, hydrolizing. agents may be allowed to act, forexample to, saponify ester groups. these groups to alkalis must be takeninto consideration so that it is advisable to work with acids or veryweak alkalis such as bicarbonates. he action qf lkalin eaee s m y. o ampso ser o snl tt diket oe up P e in the side chain,

Comp unds oht ined ic 'h ve ee yd o y T HBS an in artialan a free; ke grp ca e. es erfled..inakeown. r adic s of or anic or inorganic aeids canbe introduced e. g. of carboxylic ids such,- as acetic, propionic,butyric, crotonic, palmitic, benzoi-c or phenyl-acetic acid, of.polycarboxyl-i acids such as phthalic or suc-. lacid, o lphon e ssu h sm or toluene-sulphonic acid, oicarbonie acid or itsderivatives, oisulphuric acids, hydrohalic acids, phospho i aci s o bo ic aci 7 Freeorliberat-ed carboxylicacids can finally be carh xrlate -at st ge in theproc s. p icu arly by h a in The products of the present process suchas, for example, the, A -.1 J1cgnene=3,11,20-trione-2 ols, at1pregnadiene 3,20-idione-2l-ols, A p ee a i n e izo o e-z -01s. -presnne-w wlld -diels or their es er are t er p w tically valuablecompoundswith the action of drena corneal-hormones. o an be er e intosuch.

The followlngexamples illustratethe invention butare; not to; beregarded as limiting it in any Way, the r nts beinabr eet:

Example I 1 The following .method of preparation of the ar nt om o oday.be u d: n ne- 2 trione, melting point 154-156. 0., (obtainable, forexample, as. described in patent application Serial No. 474.326 filedEebruary 4 1943, now Patent No. 2,403,683, dated July 9, 19526) ishydrogenated in glacial acetic acid eitheriwith palladium or a littleplatinum, until one mol of hydrogen has been absorbed The product of thehydrogenation is precipitated in the usual way with about 3 parts ofdigitonin, in methanol of 80 percent strength and the precipitate splitupbydissolving in pyridine and precipitating with ether. This ud roduct.an e. used i e t c a first be separated by means of the chloride oftrimethylBmmOnium-acetic acid-.hydrazide, the resulting crystallineketone fraction being then used, By, crystallisation. or chromatographicrfliit ii ation v t e r ame- 51M ,20 ne c n beob aim-edv in, analytially pure form. It crystallizes from a mixture of acetone and ether incolourless, needles which melt at 152 C. For puriflcationalso themonoacetate is suitable; it crystallizes item a mixture oi acetone andether col urless, hexa onal, pr sm hi m l at 54? Spec tc r ation o he. at

Thereby the relative'sensitivity of +89 (in acetone). On saponification,the pure hydroxy-diketone is obtained.

5 parts of the pregnane-Bfi-ol-l1,20-dione, melting point 152 0., aredried by dissolving in hot toluene and evaporating the solution down invacuo, and then l'ieate d to 60 C. with 200 parts of very pure aceticacid containing 2 percent of water and 12 parts of lead tetra-acetatefor 24 hours, with the exclusion of moisture. The whole is thenevaporated down in vacuo and water added to. the. residue, lead dioxideseparating out. The suspension is thoroughly extracted several timeswith ether, and the extracts are Washed with water, sodium carbonatesolution and then again with water, dried with sodium sulphate andevaporated down. This neutral crude product is dissolved in absolutebenzene and purified, after the addition of pentane, by chromatographyover a column of aluminium oxide. Pregnane-3p,21- '1,20- 0n -mon acetats o ai ed t gether with some unfihan ed parent material and can beeluted from the aluminium oxide column with mixtures. of benzene, and.ether. The compoundcrystallises. from ether in plates which melt atHES-178 C.

8.5 parts of this mono-acetate aijedissolved in 10D parts of' glacialacetic acid, lOQ parts of 2 percent chromium trioxide in glacial aceticacid; (2 parts CrQa) added and the mixture allowed to stand for 16.hQursat-ZQ 'C; It then strongly: concentrated down in vacuo at a bathtemperature of 30 0., water added, and the whole extracted with ether;After having been washed, with dilute-sulphuric acid, sodiumqarbonatesolution and water, and dried-with sodium sulphate, the ethersolution is evaporated down and crystallization, which soon starts, ismade as complete as possible by the addition of some petroleum other; Inthis way. pregnanee3,11,2 0-trione-2lol-acetate is obtained incolourless crystals whichmelt at 153-155. C.

By mixing 10 parts of bromine with 384 parts of glacial e d; a normabromine sohi ioe is prepared; 9.6 parts of the product of melting point153455 0. are dissolved-in 50 parts at glacial acetic acid and twod-ropsoi the abovebrow mine solution added. After a fewminutes thecolour suddenly disappears; 48 parts of the bromine solution are. thenslowly added, cooling and rotating continually, and are almost instantaeneouslydecoloured. Crystallisation occurs afterevaporating down in vacuoat abath temperature of 25 C. The colourless crystals of these formed4-brom-;pregnane-3,l1,2,0-trione-- 21 o1 -acetate melt, after washingwith ether, at 180-.485. C.

This bromide is then boiled for 5 hours under reflux with parts ofabsolute pyridine. After evaporation down in vacuo, the residue isextracted with a large volume of ether, the ether solution washed with alittle. dilute hydrochloric acid, sodium carbonate solution and water,dried over sodium sulphate and evaporated down, The u s pur fied qmatoerhica y ove a. column of aluminium oxide, whereby the first portionseluted with benzenegive crystals which have (can-6 1 c to e The com o nis. M mesan s-74 ticosterone acetate). A sample of very pure naturaldehydro-corticosterone acetate melts under the same conditions at177-179 0., gives no melt-.-

ing point depression with the, synthetic product and has the samespecific rotation. By saponification with a methyl alcoholic solution ofhydrochloric acid or a solution of potassium bicarbonate in dilutemethyl alcohol, the free dehydrocorticosterone is obtained, melting at174-480 C. The latter compound can subsequently be converted in a knownway into any ester, for example, the propionate, palmitate, benzoate,succinate, butyrates, phosphates or carbonates. The mentioned carbonicacid esters can also be obtained directly if, instead of leadtetra-acetate, the corresponding lead tetra-acylates oraryl-iodosoacylates are used.

The same end-product is obtained starting frompregnane-3a-ol-l1,20-dione which can be obtained, for example, frompregnane-3a,l1-diol- 20-one by acetylation, oxidation and subsequentsaponification.

Example 2 25 parts of pregnane-3fl,1la-diol-20-one, colourless granulesmelting at 255 (3., [prepared for example, from 3 8,11adihydroxy-bisnorcholanic acid methyl ester (which may be obtained asdescribed in patent application Serial No. 474,726, filed February 4,1943) by degradation of the side chain using Barbier-Loquins method, ifnecessary purifying via the 3fi-acetoxy-pregnane-1la-ol- 20-one, whichcrystallizes from a mixture of ether and petroleum ether in colorlessneedles melting at 164 C. and having a specific rotation in acetone of.[c] =+115] are well dried, dissolved in 1200 parts of very pure aceticacid containing 12 parts of water and heated for 24 hours to 60 C; with60 parts of lead tetraacetate, with the exclusion of moisture.On'working up as described in Example 1, a neutral crude product isobtained from which parts of starting material are recovered bycrystallisation from ether. The amorphous mother liquors containingpregnanc- 3/3,l106,21-triol-20-one-21-mono-acetate is oxidized withaluminium phenolate and acetone. Chromatographic purification of theoxidation product so obtained gives pregnane-11a,21-diol3,20-dione-21-mono-acetate, which forms from ether colourless needles,melting point 159 C. and [oz] =+123 (acetone). By bromination andboiling with pyridine it can be converted into corticosterone acetate,melting point 157459 C. Saponification of the latter with potassiumbicarbonate in dilute methanol gives free cortiscosterone.

If pregnane 3,8,1 101,21 triol-20-one-21-monoacetate is oxidized withchromic acid instead of with aluminium phenolate and acetone,chromatographic separation of the oxidation product andrecrystallisation from a mixtureof etherand petroleum ether givespregnane-3,11,20-trione- 21-ol-acetate in colourless needles which meltat 153-155" C. Bromination and subsequent boiling with pyridine leads,as described in Example 1, to dehydrocorticosterone acetate, which meltsat 176-178 C. and gives on saponification free corticosterone.

If instead of pregnane-3 3,11a-diol-20-one there is used A-21-dicarboxy-pregnene-3-o1-20'-one (prepared, for example, from A-3-acetoxy-etiocholenic acid by treatment with sodium malonic ester andalkaline hydrolysislas starting material, 1i-anhydro-corticosteroneacetate is obtained in a similar way, with additional heating of thefirstp'roduct of the reaction for'the 'pur- 3 pose of decarboxylation.

What I claim is:

1. In a process for the manufacture of a'com- 1 pound of theadrenal'corticalhormone series, the

steps of treating a compound of the cyclopentanopolyhydro-phenanthreneseries which contains in the 3-position'a free nuclear hydroxyl group,in the 17-position an acetyl group, and as the nuclear -grouping formedwith the ring carbon atom inthe ll-position the grouping I I I HO/l withan acylate selected from the group consisting of'lead tetra-acylates andaryl-iodoso-acylates, and subsequently reacting the'resultant productwith a member selected from the group consisting of metal alcoholatesand phenolates in presence of a carbonyl compound, whereby the freenuclear 3-hydroxyl group is converted into a keto group. 3. In a processfor the manufacture of a compound of the adrenal cortical hormoneseries, the steps of treating a compound of thecyclopentano-polyhydrophenanthrene series which contains in the3-position a free nuclear hydroxyl group, in the 17-position an acetylgroup, and as the nuclear grouping formed withthering car bon atom inthe ll-position the grouping Hr l \l /23 (ll) HO with an acylateselected group the group con sisting of lead tetra-acylates. andaryl-iodosoacylates, and subsequently reacting the resultant productwith an oxidizing agent whereby at least the freenuclear hydroxyl groupin 3-position is converted into a keto group, and finally intro- .ducinga double bond into the u-DOSitlOIl to the newly formed 3-keto group byhalogenation and subsequent elimination .of hydrohalide.

4. In a process for the. manufacture of a com- 0' pound of the adrenalcortical hormone series, the

steps of treating a compound of the cyclopentano polyhydrophenanthre neserieswhich.

contains in the 3-position a free nuclear hydroxyl group, in the17-position anacetylgroup, and as the nuclear grouping-formed with-thering car bon atom in the ll-po'sition the grouping assume:

ing: of: lead; .tetrasacylatesz and: arylviodosmaci ates, andsubsequently reactin ti er-resultin quent: eliminationoft hydrohalide,.and finally:

treating the product witlra .hydrolyzing agent;

5. In a process'for'thermanufacture,of. a. compound of theadrenahcortical:hormone series,the steps of treating a compound of thecyclopentanopolyhydrophenanthrene series which contains in the3-position a free nuclear hydroxyl group, in the l'l-position an acetyl.group, and as the nucleargrouping. formed with; they ring carbon atom inthe lie-position .the grouping 11) H with: lead; tetra-acetate, andsubsequently reacting-the resultant" product with an oxidizingagentwhereby "at-least the free nuclear hydroxyl' group; in 3eposition.is converted-into; a, keto roup-,then introducinga ,doublebond: into;the st-position, to the newly formed 3-ketogroup-by halogenatlon andsubsequentv elimination; or hydrohalida. and

finally treating the product, with: a hydroiyzingagent.

6. In a process lfOl' the manufacture of a compound of the adrenalcortical hormone series, the steps of treating a compound of thecyclopentanospolyhydrophenanthrene series which contains in the3-position a free nuclear hydroxyl group, in the l'l-position an acetylgroup, and as the nuclear grouping formed with the, ringcarbon atom i inthe 1:1 -position the grouping contains in the 3-position a free nuclearhydroxyl group; in the lT-position an, acetyl group, and as the nucleargrouping formed with the ring carbon, atom in the ll-position, thegroupin with an acylate selectedirom the group consisting; of leadtetraracylates and aryl-iodosoacylates, and subsequently reacting theresultant product with an oxidizing agent whereby at least the freenuclear hydroxylgroup in 3- position is converted into a keto group,thenintroducing a double bond into the, a-position to the,

newly formed 3-keto group byhalogenation and subsequent elimination of'hydrohalide, and iinally treating the product with a hydrolyzing agent.

8. In a process for the manufacture oi a compound of the adrenalcortical hormone series,

the. steps attracting a. compound or the cyclo-.-

, the ring carbon with an acylate selected from the group consisting oflead tetra-acylates and aryl-iodosoacylates, and subsequently reactingthe resultant product with an oxidizing agent, then introducing a doublebond into the iii-position to the newly formed 3-keto group byhalogenationand subsequent elimination of hydrohalide, and finallytreating the product with a hydrolyzing agent to saponify the estergroups present and with an esterifying agent to introduce a differentacid radical.

9. The process according to claim 8 wherein the acylate is leadtetra-acetate.

10. In a process for the manufacture of a compound of the adrenalcortical hormone series, the step of treating a compound of thecyclopentano-polyhydrophenanthrene series which contains at leastin the3-position a free nuclear hydroxyl group, in the 17-position an acetylgroup, and; as the nuclear grouping formed with the; ring carbon atom inthe ll-position a member of the group consisting of o( 3 n) and "o 11 lI l (11) no with lead tetra-acetate, and subsequently reacting theresultant product with aluminum phenolate and acetone, where by the freenuclear B-hydroxyl groupv is converted into a keto group, and finallyintroducing a double bond into the a-position, to the newly formed3-keto group by bromination and subsequent dehydrobromination.

12. In a, process for the manufacture of a compound of the adrenalcortical hormone series, the step of treating a compound of thecyclopentano-polyhydrophenanthrene series which contains at least in theB positiOn a free nuclear hydroxyl group, in the 17'-po sition an acetylgroup, and as the nuclear grouping formed with o=t i (11 and withanacylate selected-from the group consisting of lead tetra-acylates andaryl-iodoso-acylates, and subsequently reacting the resultant productwith an agent selected from the group consisting of oxidizing anddehydrogenating agents.

13. The saturated pregnane-20-ones containing as sole substitutent inring C at the carbon atom 11 a free hydroxyl group, at the carbon atom21 a group which upon hydrolysis is convertible into hydroxyl and at theposition 3 a nuclear grouping containing only one oxygen atom obtainableb oxidation of a methylene group.

14. The saturated pregnane-ZO-ones containing as sole substituent inring C at the carbon atom 11 a free hydroxyl group, at the carbon atom21 an esterified hydroxyl group, and at the position 3 a nucleargrouping containing only one oxygen atom obtainable by oxidation of amethylene group.

15. The saturated pregnane-20-ones containing as sole substituent inring C at the carbon REFERENCE S CITED The following references are ofrecord in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,330,772 Bockmuhl Feb. 4, 194120 2,230,773 Bockmuhl Feb. 4, 1941 2,239,742 Serinl Apr. 29, 1941

